Understanding of the mechanisms by which T1D develops is critical to prediction, prevention and cure. The spontaneously diabetic BB rat is particularly well suited for this task. In contrast to the complexity of human and NOD mouse T1D, onset in the BB rat is limited to five genes; the MHC on chromosome 20 (Iddm1), lyp (Ian5) (Iddm2) on chromosome 4 and three susceptibility factors on chromosomes 2 (IddmS), 4 (Iddm4) and 15 (Iddm19). Our discovery in 2002 of the frameshift mutation in Ian5 (IAN4L1) that results in lymphopenia uncovered a previously unknown family of Ian genes that appear to regulate apoptosis. This program project represents three highly interactive laboratories (Seattle and Milwaukee) and one administrative core (Seattle); Project 1: Ake Lernmark will collaborate with Projects 2 and 3 to test the hypotheses that a) coordinate expression of the Ian family controls lymphocyte differentiation and maturation to generate autoreactive T cells and b) identify and characterize the three genetic factors IddmS, Iddm4 and iddm19 that confer diabetes risk. Project 2: Hartmut Weiler and Michael Michalkiewicz will collaborate with Projects 1 and 3 by (a) completing the mouse knockout (KO) of Ian5, Ian4 alone and in combination to recapitulate the diabetogenic phenotype in the mouse; (b) rescuing the expression of Ian genes in transgenic rats and (c) establish Ian anti-apoptopic activity in rat and mouse transgenic animals. Project 3: Anne Kwitek and Marty Hessner will use genomic and microarray technologies to facilitate identification of chromosome 2,15 and 4 T1D susceptibility factors in collaboration with Project 1 and 2. Our research interactions are well established and shared resources will include BB, F344 and congenic rats (Project 1), congenic lines of mice with homologous recombination of Ian genes and rat transgenic rescue of lymphopenia (Project 2), high throughput genotyping for speed congenic lines (Projects 1 and 3), microarray analysis (Project 3), quantitative RT-PCR (Project 1) and virtual mapping between human, mouse, and rat (Project 3).